Project Summary Lack of an HLA-matched donor has historically been a major obstacle to accessing allogeneic hematopoietic cell transplantation (allo-HCT) in many patients, particularly those from ethnic minorities and mixed race backgrounds. Recent work pioneered by a few centers including ours has demonstrated that the use of T- replete grafts from HLA-haploidenical donors and post-transplant cyclophosphamide to control alloreactivity (HIDTptCy) is safe with low rates of treatment related mortality and chronic GVHD. This advance has heralded the possibility of almost universal timely donor availability for patients that need allo-HCT. Furthermore, the relatively low graft-acquisition costs of HIDTptCy will improve access to allogeneic transplantation in underserved communities and developing nations. When HIDTptCy are performed for neoplastic diseases, relapse or progression of malignancy remains the most important cause of treatment failure. This is particularly so when non-myeloablative or reduced-intensity preparative regimens (RIC) are used. Administration of proteasome inhibitor drugs post allo-HCT may reduce relapse through direct anti-cancer activity as well potential stimulation natural killer (NK) cell alloreactivity. Furthermore, proteasome inhibitors have been demonstrated to inhibit graft-versus host disease. In an institutional pilot trial we have assessed the safety of the administration of the orally bioavailable proteasome inhibitor ixazomib for 12 months following HIDTptCy using RIC. Preliminary analysis of this trial has shown minimal toxicity with relatively low rates of relapse albeit with short follow-up. Another agent with potential to decrease relapse rates post HIDTptCy is the anti-SLAMF7 monoclonal antibody elotuzumab. This antibody has been shown to activate NK cells through binding of this receptor and may be particularly effective post HIDTptCy given the existing evidence that NK cell alloreactivity is important at preventing relapse in this setting. The activity of elotuzumab may also be augmented by co- exposure to a proteasome inhibitor. The proposed trial will be a randomized phase II study comparing the post- transplant administration of ixazomib versus elotuzumab versus ixazomib + elotuzumab during the first year post HIDTptCy using RIC for acute myeloid leukemia. It will specifically test the hypothesis that these agents alone or in combination will decrease the relapse rate which has been previously documented to be 43% at 12 months in this setting without use of these novel agents. Furthermore, it will test the hypothesis that these agents will not increase the rate of non-relapse mortality and will be well tolerated. Accrual to the three arms will be stratified for factors shown to be significant predictors of relapse following HIDTptCy using RIC for AML in multivariable analysis. This trial will also determine which of the three arms has the most promising outcomes and thus merits formal comparison to the standard-of care (HIDTptCy using RIC for AML without post-transplant novel agent use) in a future randomized phase III trial.